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CNS [182]. Compared with neuronal specific EPOR immunoreactivity in the
human adult brain, EPORs have been detected in microvessels and neuronal
fibers after acute injury, and in astrocytes of old infarct areas [165]. In response
to hypoxia or anemic stress, neuronal EPOR expression is modified by a rela-
tively higher increase in transcripts containing the appropriately spliced 5' cod-
ing region (exons 1 to 2) than that of the upstream transcripts (exon A). This
indicates a shift under injury towards increased sensitivity to EPO [166].
In
vitro
, pro-inflammatory cytokines such as tumor necrosis factor (TNF)-
also
α
up-regulate EPOR expression in human neuronal cells [183].
The activation of EPOR in neuronal cells is associated via JAK-2 with the
phosphorylation of I-
B and results in the cytoplasm-to-nucleus translocation
κ
of NF-
B. Hereby, the transcription of genes which are associated with neu-
ronal cell protection becomes activated [184]. Such a cross-talk phenomenon
between JAK-2 and NF-
κ
B signaling has not been described in non-neuronal
cells, suggesting that neuro-specific proteins link both pathways together [11].
In transmitting the cell-protective effects of EPO in the injured CNS, EPOR
expression on vascular smooth muscle cells is important, because EPO nor-
malizes the auto-regulation of the cerebral blood flow after acute brain injury
[185]. EPOR expression on capillary endothelial cells in the CNS may con-
tribute to the neuroprotection as well, because these cells may be stimulated to
produce neutrophins such as brain-derived neurotrophic factor (BNDF) [186].
The specific role of a second,soluble form of EPOR expressed in (murine)
brain capillary cells needs additional investigations [103].
κ
Eye
Expression of both EPO and EPOR in the human eye has been detected by RT-
PCR analysis in tissue specimens from fetuses between six and 16 weeks of
gestation [161]. While further data on the biology of EPO in the human eye are
not available yet, animal studies indicate an important role of EPO as an
endogenous retinal survival factor [12, 102].
In neonatal rats, immunohistochemistry revealed EPOR expression in dif-
ferent layers of the retina, most intensive in the retinal ganglion cell layer, and
less intensive in the inner and outer plexiform layers and the inner portion of
the inner segments [187].
In vitro
, rEPO stimulates the neurite outgrowth in
neurons of the rat retina [187].
In adult mammalian (mouse) retina, EPOR is localized in the rod inner seg-
ment of photoreceptor cells and in presynaptic complexes of photoreceptors.
EPOR has also been detected, but with lower immunohistochemical staining
intensity in the inner nuclear layer [188]. EPO expression in the retina increas-
es after exposure to hypoxia, and hypoxic pretreatment protects murine pho-
toreceptor cells from apoptotic cell death after exposure to damaging light lev-
els
in vivo
. The systemic application of rEPO one hour before or after light
